Kinase regulation of human MHC class i molecule expression on cancer cells Journal Article
| Authors: | Brea, E. J.; Oh, C. Y.; Manchado, E.; Budhu, S.; Gejman, R. S.; Mo, G.; Mondello, P.; Han, J. E.; Jarvis, C. A.; Ulmert, D.; Xiang, Q.; Chang, A. Y.; Garippa, R. J.; Merghoub, T.; Wolchok, J. D.; Rosen, N.; Lowe, S. W.; Scheinberg, D. A. |
| Article Title: | Kinase regulation of human MHC class i molecule expression on cancer cells |
| Abstract: | The major histocompatibility complex I (MHC-1) presents antigenic peptides to tumor-specific CD8-T cells. The regulation of MHC-I by kinases is largely unstudied, even though many patients with cancer are receiving therapeutic kinase inhibitors. Regulators of cell-surface HLA amounts were discovered using a pooled human kinome shRNA interference-based approach. Hits scoring highly were subsequently validated by additional RNAi and pharmacologic inhibitors. MAP2K1 (MEK), EGFR, and RET were validated as negative regulators of MHC-I expression and antigen presentation machinery in multiple cancer types, acting through an ERK output-dependent mechanism; the pathways responsible for increased MHC-I upon kinase inhibition were mapped. Activated MAPK signaling in mouse tumors in vivo suppressed components of MHC-I and the antigen presentation machinery. Pharmacologic inhibition of MAPK signaling also led to improved peptide/MHC target recognition and killing by T cells and TCR-mimic antibodies. Druggable kinases may thus serve as immediately applicable targets for modulating immunotherapy for many diseases. © 2016 American Association for Cancer Research. |
| Journal Title: | Cancer Immunology Research |
| Volume: | 4 |
| Issue: | 11 |
| ISSN: | 2326-6066 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2016-11-01 |
| Language: | English |
| DOI: | 10.1158/2326-6066.cir-16-0177 |
| PROVIDER: | scopus |
| PMCID: | PMC5110210 |
| PUBMED: | 27680026 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 May 2017 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work